Abstract: The enzyme Sialic acid acetylesterase maintains peripheral B cell tolerance and prevents the activation of B cells that see self antigens weakly. This enzyme is of relevance in both murine and human B cells. Inhibiting this esterase may permit the activation of B cells that see conserved but weak epitopes on HIV gp120. The SIAE gene will be knocked down in humanized mice. Both SIAE knockdown humanized mice and Siae mutant conventional mice will be immunized with gp140 trimers in an attempt to ask if inhibition of SIAE favors the generation of neutralizing antibodies against HIV. A novel strategy for HIV vaccination is proposed, that may permit the induction of protective neutralizing antibodies.